Early Growth Response-1 (EGR-1) Controls Synoviocyte Apoptosis, and Its Expression Is Regulated by the Direct Binding of Fibroblast Growth Factor-1 (FGF1) or Insulin-Like Growth Factor-1 (IGF1) to Integrin αvβ3

Shino Tanaka¹, Jun Saegusa¹, Seiji Kawano¹, Yoshikazu Takada², Shunichi Kumagai³ and Akio Morinobu¹, ¹Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ²Dermatology, University of California, Davis, School of Medicine, Sacramento, CA, ³The Center of Rheumatic Diseases, Shinko Hospital, Kobe, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Apoptosis, growth factors and synovial cells, synovial fluid

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Growth factors such as fibroblast growth factor (FGF) and insulin-like growth factor (IGF) are of interest in the initiation and development of rheumatoid arthritis (RA) synovial hyperplasia, because of their potent mitogenic and angiogenic activities. The traditional understanding of FGF and IGF signaling has held that their binding to their respective receptor (i.e., the FGF receptor [FGFR] or the IGF receptor [IGFR]) is sufficient to initiate signaling. We recently demonstrated that FGF1 binds directly to integrin αvβ3, and that an integrin-binding-defective FGF1 mutant (FGF^R50E) cannot induce cell proliferation, even though the mutant still binds FGFR; this is also true for IGF1. In both cases, a ternary complex, FGF1-FGFR-integrin αvβ3 or IGF1-IGFR-integrin αvβ3, was formed. However, the mechanism underlying the cross-talk between growth-factor-receptor signaling and integrin signaling is unknown. Here we investigated how the growth factor-integrin αvβ3 interaction is involved in growth-factor signaling in RA synoviocytes.

Methods: Several mutations were introduced at the interface of FGF1 or IGF1 with integrin αvβ3, and integrin-binding-defective FGF1 and IGF1 mutants (FGF^R50E and IGF^R36E/R37E) were generated. RA synoviocytes were stimulated with FGF1 or FGF^R50E, and comprehensive gene-expression profiling was performed by cDNA microarray. Intracellular signaling in synoviocytes treated with FGF1, FGF^R50E, IGF1, and IGF^R36E/R37Ewas evaluated by real-time PCR and Western blot analyses. Synoviocytes transfected with scramble siRNA or early growth response-1 (EGR-1)-specific siRNA were treated with various apoptotic stimuli, and cell viability was measured by the WST-8 assay.

Results: The integrin-binding-defective mutants (FGF^R50E and IGF^R36E/R37E) showed a markedly reduced ability to induce the cell proliferation of RA synoviocytes. The cDNA microarray analysis showed significantly reduced EGR-1 mRNA expression in the FGF^R50E-treated synoviocytes. Furthermore, EGR-1 mRNA and protein were rapidly induced in RA synoviocytes in response to FGF1 or IGF1, but the EGR-1 expression was significantly impaired in FGF^R50E– or IGF^R36E/R37E-treated synoviocytes. In addition, the down-regulation of EGR-1 by siRNA inhibited the apoptosis of synoviocytes treated with H₂O₂ or doxorubicin.

Conclusion: EGR-1 plays a pivotal role in synoviocyte apoptosis, and its expression is regulated by the direct binding of FGF1 or IGF1 to integrin αvβ3. This integrin-growth factor interaction may be a novel therapeutic target for RA.

Disclosure:

S. Tanaka,
None;

J. Saegusa,
None;

S. Kawano,
None;

Y. Takada,
None;

S. Kumagai,
None;

A. Morinobu,
None.

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